Genomic profiling of mycosis fungoides identifies patients at high risk of disease progression.

ABSTRACT: Mycosis fungoides (MF) is the most prevalent primary cutaneous T-cell lymphoma, with an indolent or aggressive course and poor survival. The pathogenesis of MF remains unclear, and prognostic factors in the early stages are not well established. Here, we characterized the most recurrent genomic alterations using whole-exome sequencing of 67 samples from 48 patients from Lille University Hospital (France), including 18 sequential samples drawn across stages of the malignancy. Genomic data were analyzed on the Broad Institute's Terra bioinformatics platform. We found that gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), or mutations in JUNB and TET2 are associated with high-risk disease stages. Furthermore, gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), and del6q16.3 (TNFAIP3) are coupled with shorter survival. Del6q16.3 (TNFAIP3) was a risk factor for progression in patients at low risk. By analyzing the clonal heterogeneity and the clonal evolution of the cohort, we defined different phylogenetic pathways of the disease with acquisition of JUNB, gain10p15.1 (IL2RA and IL15RA), or del12p13.1 (CDKN1B) at progression. These results establish the genomics and clonality of MF and identify potential patients at risk of progression, independent of their clinical stage.

Characteristics and incidence of infections in patients with multiple myeloma treated by bispecific antibodies: a national retrospective study.

OBJECTIVES: Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. METHODS: A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. RESULTS: Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of ≥3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% (n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38-3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3-0.94 and HR = 0.65; 95% CI, 0.46-0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27-3.19). DISCUSSIONS: The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS.

Current state and next-generation CAR-T cells in multiple myeloma.

Chimeric antigen receptor T cells (CAR-T cells) have emerged as a potentially transformative new approach to treating hematological malignancies. Ide-cel, an autologous B cell maturation antigen (BCMA) targeting CAR-T cells, has recently been approved to treat multiple myeloma (MM). Here, we review the main clinical trials of CAR-T cells in MM with the most advanced autologous BCMA-directed ide-cel and cilta-cel, the human CARs orva-cel and CT053, the alternative manufacturing process with P-BCMA-101 and bb21217, the dual CAR GC012F and the allogenic BCMA-directed CAR-T cells ALLO-715. In light of those clinical data, we provide an overview of CAR-T cells' main potential resistance mechanisms, including antigen loss, antigen spreading, anti-CAR antibodies, CAR-T cell exhaustion, and the emergence of a non-permissive microenvironment. Finally, we describe the principal area of research to build the next generation of CAR-T cells, with armored-, gated- or commuting-CARs, CARs associated with knock out of specific genes, and CAR-T cells made from γδT cells or NK cells.

[Bispecific antibodies in multiple myeloma]. / Myélome multiple et anticorps bispécifiques.

Immunotherapies have recently emerged as potential game changers in the treatment of multiple myeloma (MM). Those include monoclonal antibodies (targeting CD38 or CS1), bispecific antibodies (BsAb, mainly targeting BCMA, GPRC5D or FcRH5), antibody-drug conjugate (mainly targeting BCMA) and CAR-T cells (mainly targeting BCMA). BsAb have the capacity to bind two different antigens, one at the tumor cell surface and one on T cells (CD3), recreating the immune synapse. In this article, we discuss the main clinical data on BsAb in MM, as well as their different constructs and the potential mechanism of resistance.

Discontinuation of antimicrobial therapy in adult neutropenic haematology patients: A prospective cohort.

OBJECTIVES: Antibiotics for febrile neutropenia (FN) in acute myeloid leukaemia (AML) patients undergoing intensive chemotherapy are usually maintained until neutropenia resolution, because of the risk of uncontrolled sepsis in this vulnerable population. This leads to unnecessarily prolonged antimicrobial therapy. METHODS: Based on ECIL-4 recommendations, we modified our management strategy and discontinued antibiotics after a pre-established duration in patients treated for a first episode of FN between August 2014 and October 2017. RESULTS: Antibiotics were stopped during 62 FN episodes, and maintained in the control group (n = 13). Median age of patients was 54 years. A total of 39 (63%) patients received induction and 23 (37%) consolidation chemotherapy; 36 (58%) patients had fever of unknown origin. Median neutropenia length was 26 days (IQR 24-30). Antibiotics were started at day 9 (IQR 5-13). Most patients received piperacillin-tazobactam (56%) or cefepime (32%). Antimicrobial therapy was longer in the control group than in the policy compliant group, 10 (IQR 7-16) vs. 19 days (IQR 15-23), P = 0.0001. After antibiotics discontinuation, 20% patients experienced fever recurrence, within 5.5 days (IQR 3-7.5). None of these febrile episodes were severe and 80% patients remained afebrile, with neutrophil recovery occurring within 5 days (IQR 2-8.5). Overall, 287 antibiotics days were spared; this represents 49% of all days with antibiotics. No patient had died at day 30 from intervention; six died during late follow-up, two from graft-versus-host disease and four from relapsed or refractory leukaemia. CONCLUSIONS: Discontinuing antibiotics in neutropenic AML patients treated for a first episode of FN is safe, and results in significant antibiotic sparing.

Deregulation and Targeting of TP53 Pathway in Multiple Myeloma.

Multiple Myeloma (MM) is an incurable disease characterized by a clonal evolution across the course of the diseases and multiple lines of treatment. Among genomic drivers of the disease, alterations of the tumor suppressor TP53 are associated with poor outcomes. In physiological situation, once activated by oncogenic stress or DNA damage, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. Its inactivation participates to drug resistance in MM. The frequency of TP53 alterations increases along with the progression of the disease, from 5 at diagnosis to 75% at late relapses. Multiple mechanisms of regulation lead to decreased expression of p53, such as deletion 17p, TP53 mutations, specific microRNAs overexpression, TP53 promoter methylations, and MDM2 overexpression. Several therapeutic approaches aim to target the p53 pathway, either by blocking its interaction with MDM2 or by restoring the function of the altered protein. In this review, we describe the mechanism of deregulation of TP53 in MM, its role in MM progression, and the therapeutic options to interact with the TP53 pathway.